Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2023;13(1):e2023064 1 Narrative Review of Drug-Associated Nail Toxicities in Oncologic Patients Anastasia Emvalomati1, Valentina Oflidou1, Chryssoula Papageorgiou1, Christina Kemanetzi1, Maria Giannouli1, Evangelia Kalloniati1, Konstantinos Efthymiadis2, Chrysanthi Koukoutzeli2, Eleni Timotheadou2, Anastasia Trigoni1, Aikaterini Patsatsi1, Elizabeth Lazaridou1, Zoe Apalla1, MyrtoTrakatelli1 1 Second Department of Dermatology, Aristotle University of Thessaloniki, “Papageorgiou” General Hospital, Thessaloniki, Greece 2 Department of Medical Oncology, Aristotle University of Thessaloniki, “Papageorgiou” General Hospital, Thessaloniki, Greece Key words: nail toxicity, nail changes, chemotherapy, targeted treatment, immune checkpoint inhibitors Citation: Emvalomati A, Oflidou V, Papageorgiou C, et al. Narrative Review of Drug-Associated Nail Toxicities in Oncologic Patients. Dermatol Pract Concept. 2023;13(1):e2023064. DOI: https://doi.org/10.5826/dpc.1301a64 Accepted: August 23, 2022; Published: January 2023 Copyright: ©2023 Emvalomati et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: Z. Apalla and M. Trakatelli equally contributed as senior authors. Corresponding Author: Myrto Trakatelli, PhD, Second Dermatology Department, Aristotle University, 76 Agiou Pavlou, Pavlos Melas, 564 29, Thessaloniki, Greece. Tel. +302313323873, Fax: +302310991473 E-mail: mtrakatelli@hotmail.com Introduction: Nail toxicity represents one of the most common cutaneous adverse effects of both classic chemotherapeutic agents and new oncologic drugs, including targeted treatments and immunotherapy. Objectives: We aimed to provide a comprehensive literature review of nail toxicities derived from conventional chemotherapeutic agents, targeted therapies (EGFR inhibitors, multikinase inhibitors, BRAF and MEK inhibitors) and immune checkpoint inhibitors (ICIs), including clinical presentation, implicated drugs and approaches for prevention and management. Methods: Retrieved literature from PubMed registry database was reviewed to include all articles published up to May 2021 relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of oncologic treatment-induced nail toxicity. The internet was searched for relevant studies. Results: A wide spectrum of nail toxicities is associated with both, conventional and newer anticancer agents. The frequency of nail involvement, especially with immunotherapy and new targeted agents re- mains unknown and patients with different cancer types receiving different regimens may develop the same nail disorder, whereas patients with the same type of cancer under the same chemotherapeutic treat- ment may develop different types of nail alterations. The underlying mechanisms of the varying individu- al susceptibility and the diverse nail responses to various anticancer treatments need further investigation. Conclusion: Early recognition and treatment of nail toxicities can minimize their impact, allowing better adherence to conventional and newer oncologic treatments. Dermatologists, oncologists and other implicated physicians should be aware of these burdensome adverse effects in order to guide management and prevent impairment of patients’ quality of life. ABSTRACT 2 Review | Dermatol Pract Concept. 2023;13(1):e2023064 Introduction Nail toxicity represents one of the most common cutaneous adverse effects of both classic chemotherapeutic agents and new oncologic drugs, including targeted treatments and im- munotherapy [1]. While drug-associated nail toxicity is al- most never life-threatening, it significantly impairs patients’ quality of life, often restricting their daily life and self-care activities. Dermatologists, oncologists and other implicated physi- cians should be aware of these burdensome adverse effects in order to guide management and prevent impairment of patients’ quality of life. Early recognition and treatment can minimize the impact of these toxicities, allowing better ad- herence to conventional and newer oncologic treatments. The aim of this article is to provide a comprehensive liter- ature review of nail toxicities derived from conventional chemotherapeutic agents, targeted therapies (EGFR inhibi- tors, multikinase inhibitors, BRAF and MEK inhibitors) and immune checkpoint inhibitors (ICIs), including clinical pre- sentation, implicated drugs and approaches for prevention and management. Materials and Methods Search Strategy and Study Selection The retrieved literature was reviewed to include all articles relevant to the clinical presentation, diagnosis, incidence, prevention, and treatment of oncologic treatment-induced nail toxicity. The PubMed registry database was searched for relevant studies published up to May 2021. The literature ev- idence predominantly comprises case reports, case series and systematic reviews. The following Medical Subject Headings search terms were used: nails, nail changes, nail toxicity; che- motherapy, chemotherapeutic drugs/agents, antineoplastic agents. The “related articles” function in PubMed was used to broaden the search, and all retrieved abstracts, studies and citations were reviewed. In addition, we identified other rel- evant studies by searching the reference lists of the relevant articles and by contacting known experts in the field. No language restrictions were applied. Data Extraction Two reviewers independently assessed all relevant stud- ies and specifically extracted data regarding study design, study population characteristics, inclusion and exclusion criteria, nail toxicity parameters, class of chemotherapeu- tic drugs and their mechanism of action. The individually recorded decisions of both reviewers were compared and any disagreements were resolved by the other reviewers. Study authors were contacted for additional information when necessary. Discussion Conventional Chemotherapeutic Drugs (Figure 1) Cancer therapy has always been a challenging area in clin- ical medicine and research. Traditionally, chemotherapeutic drugs work by disrupting specific phases of the cell cycle in actively dividing cancer cells (Table 2). Conventional chemo- therapeutic drugs continue to be an important part of cancer management but may cause various cutaneous and append- ageal reactions including nail toxicity. Nail involvement in cancer therapy is reported in fragmented literature from all over the world. Although it is mostly of cosmetic concern, at times it may require alteration or modification of the ther- apy, especially if very painful or functionally debilitating nail toxic effects are present. Pain and associated discomfort impair patients’ quality of life, commonly resulting in the inability to perform daily activities [2]. The nail apparatus is characterized by the presence of con- tinuously dividing nail matrix cells, thus making it an easy target of the antimitotic activity of chemotherapeutics [3]. Nail changes in the context of chemotherapy involve multiple or even all 20 nails and usually appear in a temporal rela- tion with the drug intake, due to an acute insult of the nail matrix epithelium. Effects mostly subside upon withdrawal of the responsible chemotherapeutic agent, but occasionally may persist. Because of the specific kinetics of nail formation and growth, it is important to note that the occurrence of these nail toxic effects is often delayed relative to treatment initiation. Clinical presentation varies, depending on the nail struc- ture affected and the severity of the insult [4]. In terms of to- pography, when the nail bed is affected, onycholysis, apparent leukonychia and splinter haemorrhages may be observed. Toxicity targeting the nail matrix may result in the appearance of Beau’s lines, onychomadesis, true leukonychia, slower nail growth, nail thinning, brittle nails and melanonychia. Finally, adverse effects involving the perionychium may result in par- onychia and pyogenic granuloma [5, 6]. A combination of the aforementioned nail changes is frequent. The most common nail changes reported in the literature include leukonychia, Beau’s lines, brittle thin nails, and nail hyperpigmentation, which may be diffuse or horizontal [7- 10]. Taxanes and an- thracyclines are the antineoplastic regimens mostly associated with nail changes. However, considering that a majority of the reported patients were on multiple chemotherapeutic agents, pinpointing the offensive drug was not always feasible. There- fore, a combination of agents was implicated in most cases. Alkylating Agents Classical Alkylating: Cyclophosphamide Classical alkylating agents attach an alkyl group to the guanine base of DNA and are used to treat leukaemia, lym- phoma, Hodgkin disease, multiple myeloma, sarcoma, and Review | Dermatol Pract Concept. 2023;13(1):e2023064 3 Figure 1. Nail toxicities due to conventional chemotherapeutic drugs. A. Muehrcke’s lines due to treatment with cisplatin: Transversal white lines with healthy nail bed between them. B. Dermosopic examination of the same patient with clear visualization of the leukonychia in the form of Muehrcke’s lines. C. Red-brown discoloration of the nails associated with painful subungual hematomas and onycholysis following treatment with taxol. D. Dermoscopic image of the chemotherapy-induced central subungual hematoma that differs from traumatic subungal hematoma: note the bright red color with an orange/brown halo (in trauma: dark violet with globular pattern accompanied by transversal whitish line). E. Longitudinal melanonychia following cyclophosphamide treatment. F. Dermoscopy image of the cyclophosphamide-induced melanonychia with a homogenous brown band with absence of Hutchinson or micro-Hutcinson’s sign. Borders appear blurry but this may happen in the great toenail due to thickness of the nail plate. This is a false positive sign that should be interpreted together with the clinical history of the patient. Table 1. Proposed management algorithm for taxane-related onycholysis [38]. Grade 0* • Preventive nail care instructions given • Frozen gloves should be considered Grade 1* Asymptomatic separation of the nail bed from the nail plate or nail loss • Continue drug at current dose and monitor for change in severity • Obtain bacterial/fungal cultures if infection is suspected; apply topical antibiotics or fungal agent • Reassess after 2/3 weeks. If reaction worsens proceed to next step Grade 2* Symptomatic separation of the nail bed from the nail plate or nail loss; Limiting instrumental activities of daily living • Continue drug at current dose and monitor for change in severity • Obtain bacterial/fungal cultures if infection is suspected • If infection, begin oral antibiotics with anti –Staphylococcus aureus and gram-positive coverage • If painful hematoma or subungual abscess is suspected, partial or total nail avulsion is required • Pain control • Reassess after 2 weeks; if reactions worsen or do not improve interrupt treatment until severity decreases to Grade 0-1 Grade 3* Severe pain and/or superinfection; Limiting self-care activities of daily living Interrupt treatment until severity decreases to Grade 0-1, obtain bacterial/fungal cultures if infection is suspected and continue treatment of nail reaction with the following: • If infection, begin oral antibiotics with anti –Staphylococcus aureus and gram-positive coverage • If painful hematoma or subungual abscess is suspected, partial or total nail avulsion is required • Pain control • Reassess after 2 weeks; if reactions worsen or do not improve, consider dose interruption or discontinuation per protocol and switch to another antineoplastic agent *From nail loss clinical grading, Common Terminology Criteria for Adverse Events (CTCAE), V4.02 4 Review | Dermatol Pract Concept. 2023;13(1):e2023064 Table 2. Conventional chemotherapeutic drugs, mechanism of action and associated nail toxicity. Drug Class Chemotherapeutic Drugs Mechanism Of Action Nail Disorders Alkylating agents Classical alkylating Platinum agents Cyclophosphamide Cisplatin Carboplatin Oxaliplatin Crosslink with DNA molecules and damage cells in all phases of the cell cycle Diffuse hyperpigmentation Longitudinal melanonychia Beau’s lines Onychomadesis Mees’ lines Muehrcke’s lines Onycholysis Beau’s lines Hyperpigmentation Muehrcke’s lines Diffuse hyperpigmentation Muehrcke’s lines Antimetabolites Analogs Fluorouracil Pemetrexed 5-Fluorouracil Capecitabine Tegafur Substitute building blocks of DNA and RNA and damage cells in the S phase Melanonychia Onycholysis Beau’s lines Muehrcke’s lines Paronychia Subungual hyperkeratosis Hyperpigmentation Half and half nails Onycholysis Onychomadesis Onycholysis Hyperpigmentation Longitudinal melanonychia Antitumor antibiotics Anthracyclines Bleomycin Doxorubicin Daunorubicin Epirubicin Intercalate with DNA base pairs and interfere with topoisomerase II in all cell cycle phases Induce DNA strand breaks at G2 phase Diffuse hyperpigmentation Beau’s lines Mees’ lines Muehrcke’s lines Diffuse hyperpigmentation Mees’ lines Beau’s lines Diffuse hyperpigmentation Longitudinal melanonychia Beau’s lines Mitotic inhibitors Taxanes Vinca alkaloids Docetaxel Paclitaxel Vincristine Prevent the formation of spindles or microtubules during the M phase Diffuse hyperpigmentation Beau’s lines Onychomadesis Mees’ lines Paronychia Subungual hyperkeratosis Pyogenic granuloma Subungual & splinter hemorrhage Onycholysis/Exudative Onycholysis Brittle nails Onychorrhexis Koilonychia Diffusehyperpigmentation Longitudinal melanonychia Beau’s lines Onychomadesis Mees’ lines Muehrcke’s lines Topoisomerase inhibitors Topoisomerase II Etoposide Interfere with topoisomerase I or II during DNA replication in all cells in the S or G2 phase Paronychia Review | Dermatol Pract Concept. 2023;13(1):e2023064 5 and are used to treat various hematologic malignancies and solid tumors. Their main adverse effect is cardiotoxicity, which is limited in the liposomal pegylated or encapsulated form of anthracyclines used for non-Hodgkin lymphoma, multiple myeloma, NSCLC, AIDS-related Kaposi sarcoma, and refractory ovarian cancer. Both drugs are administered intravenously [12]. Doxorubicin may cause diffuse hyper- pigmentation, Beau’s lines, Mees’ lines or Muehrcke’s lines. Daunorubicin may also cause diffuse hyperpigmentation or Mees’ lines (Table 2). Bleomycin Bleomycin is a glycopeptide produced by the bacterium Streptomyces verticillus and is used for the treatment of squamous cell carcinoma, lymphoma, testicular carcinoma, and malignant pleural effusion. It can be administered intra- venously, intramuscularly, intraperitoneally, intrapleurally, or given as an intralesional injection in recalcitrant warts, keloids, and scars [17]. Toxicity to bleomycin occurs in the lungs and skin because these organs lack bleomycin hydro- lase, an inactivating enzyme [18]. Pulmonary fibrosis is a serious complication of high doses (>400 units), while cuta- neous reactions usually occur between 200 to 300 units [17]. Bleomycin may cause nail dystrophy, and horizontal or vertical nail pigmentation [17] (Table 2). Mitotic/Spindle Inhibitors Taxanes: Paclitaxel and Docetaxel Taxanes are among the most commonly prescribed antican- cer drugs and were initially derived from yew trees. Pacli- taxel is a natural extract derived from the bark of the pacific yew tree (Taxus brevifolia) that became commercially avail- able in 1992. On the other hand, docetaxel is a semisyn- thetic analogue of paclitaxel synthesized from the needles of the European yew tree (Taxus baccata). Both drugs act as antimicrotubule agents by promoting the polymerisation of tubulin into highly stable intracellular microtubules, thus disrupting mitosis and normal cell division, and eventually leading to cell death [19- 21]. Because of their highly hydro- phobic properties, they require the use of solvents (non-ionic polyoxyethylated castor oil -Cremophor EL®- for pacli- taxel; non-ionic surfactant polysorbate 80 for docetaxel) to facilitate parenteral administration. The drugs are approved for a number of indications in the US and Europe. Paclitaxel was the first taxane discovered, is generally administered by weekly infusion (80 mg/m2) and is currently approved by the US Food and Drug Administration for the treatment of breast cancer, NSCLC, AIDS-related Kaposi sarcoma, and ovarian cancer. Docetaxel, developed later, is infused (100 mg/m2) every three weeks and is used for the management of advanced breast, gastric, NSCLCs, hormone-refractory prostate cancers of the lung, breast and ovary [11]. All can be ad- ministered intravenously, though cyclophosphamide can be also taken orally [12]. Cyclophosphamide may cause diffuse hyperpigmentation, longitudinal melanonychia, Beau’s lines, onychomadesis, Mees’ lines, Muehrcke’s lines and onycholy- sis (Table 2). Platinum Agents: Cisplatin, Carboplatin, and Oxaliplatin Platinum agents form reactive platinum complexes that crosslink with DNA molecules, inhibiting DNA synthesis and repair, and are given intravenously. Cisplatin is an older drug that causes many side effects (eg, ototoxicity, neurotox- icity, nephrotoxicity, and emetogenicity) and is used to treat a wide variety of solid tumors. Cisplatin may cause Beau’s lines, hyperpigmentation or Muehrcke’s lines. Carboplatin and oxaliplatin are newer-generation platinum agents with less toxicity [13]. These chemotherapeutic agents may cause diffuse hyperpigmentation or Muehrcke’s lines (Table 2). Antimetabolites Analogs: Pemetrexed Pemetrexed is an intravenously administered folate analogue that interferes with enzymes required for pyrimidine and pu- rine synthesis, and is used for the treatment of mesothelioma, non-small cell lung carcinoma (NSCLC), and breast, head, and neck carcinoma. Uncommon reported nail reactions to peme- trexed include melanonychia and onycholysis [14] (Table 2). Fluorouracil: 5-Fluorouracil, Capecitabine and Tegafur 5-Fluorouracil (5-FU) is a pyrimidine analog that inhibits the enzyme thymidylate synthase, thereby interrupting thymi- dine synthesis required for DNA replication, and can cause myelosuppression, diarrhea, mucositis, and dermatitis [12]. Capecitabine and Tegafur are orally administered pro- drugs especially used for colon and gastrointestinal neo- plasms. They are designed to be well absorbed from the gastrointestinal tract and converted to 5-FU in the liver or within the tumor at lower concentrations than 5-FU intrave- nous dosages, thereby minimizing toxicity [15]. In the nails, 5-FU may cause diffuse melanonychia, trans- verse bands, or half and half-like nails (Lindsay nails), while there have also been reports of onycholysis, paronychia, and thickening of the nail with its use [16]. Capecitabine and tegafur also cause longitudinal melanonychia [16]; however, onycholysis and onychomadesis have only been seen with capecitabine [12] (Table 2). Antitumor antibiotics Anthracyclines: Doxorubicin and Daunorubicin The anthracyclines doxorubicin and daunorubicin are de- rived from the bacterium Streptomyces peucetius var. caesius 6 Review | Dermatol Pract Concept. 2023;13(1):e2023064 II inhibitors frequently induce rearrangements of the mixed lineage leukemia gene and can cause a secondary leukemia side effect [36]. Etoposide has been approved by the US Food and Drug Administration to be used in combination with other medications to treat small cell lung cancer and testicu- lar cancer. It is a derivative of podophyllotoxin. It is typically taken orally, but can also be administered intravenously, though care must be used to prevent extravasation because it is an irritant and can cause tissue damage. Nail toxic side effect caused by etoposide is paronychia [12] (Table 2). Targeted Biologic Drugs (Figure 2) Targeted cancer therapies are drugs that selectively block specific parts of cancer cells, such as proteins or genes, that help cancers grow and spread. Targeted biologic therapies are well-known causing factors of cutaneous adverse effects, including changes in the nail apparatus [37, 38]. Cutaneous and nail reactions may be attributed to the mode of action of these regimens that target specific mol- ecules that are also expressed in the skin and appendageal epithelium. EGFR-Inhibitors Epidermal growth factor receptor inhibitors (gefitinib, erlo- tinib, cetuximab, panitumumab) block the signal transduc- tion pathway, needed for cell proliferation, migration and angiogenesis of tumor cells [37- 40]. Gefitinib and erlotinib are orally administered EGFR tyrosine kinase inhibitors, whilst cetuximab and panitu- mumab are humanized monoclonal antibodies that are given intravenously. These regimens are used for colorectal cancer, breast cancer, non-small cell lung cancer (NSCLC), pancreatic cancer, and head and neck squamous cell carci- noma (SCC) [38- 40]. A common nail reaction in the context of EGFR inhibition is paronychia, representing the second most frequent skin toxicity induced by EGFR after papulo- pustular eruption [41]. It involves the nails and the digits, with the first digit being the site most commonly affected. Other ungual adverse reactions include discoloration, pit- ting, nail thinning/fragility (inhibition of nail matrix kera- tinocytes), periungual pyogenic granuloma (an overgrowth of granulation tissue and a formation of painful, bleeding nodule), cracked and swollen nail folds and cuticles, par- tial or complete loss of nails and ingrowth of nails [37, 38] (Table 3). The aforementioned alterations may appear 1 to 2 months after treatment initiation and affect about 15% of patients [38]. Secondary infection is not unusual and in this scenario, a culture swab is recommended. In pa- tients treated with Cetuximab that developed paronychia, Staphylococcus aureus was found in 23%, while 31% had coagulase-negative, Gram (+) bacteria (nosocomial coloni- zation) [37, 38]. Prevention of superinfection was achieved cancer, and advanced head and neck squamous cancer [22]. Docetaxel appears to have recently become most specifically associated with nail toxicity, occurring in up to 30 – 40% of patients [6, 23]. Nail changes with taxanes are very common with some series reporting rates as high as 89% after three treatment cycles [24- 29]. These chemotherapeutic agents may cause diffuse hyperpigmentation, Beau’s lines, onychomadesis, Mees’ lines, paronychia, subungual hyperkeratosis, pyogenic granuloma, subungual & splinter hemorrhage, onycholysis/ exudative onycholysis, brittle nails, onychorrhexis or koilon- ychia (Table 2). Nab-paclitaxel is a novel, solvent-free, albumin-bound, colloidal suspension (with a size of 130 nm) of paclitaxel that has led to a significant improvement in progression-free survival, median overall survival, and overall response rates in patients with metastatic breast and pancreatic cancers [21, 30]. It has received FDA and EMA approvals for the treatment of certain forms of both cancers [30]. It is also approved in the US for metastatic non-small cell lung can- cer and is still under evaluation for several other indications, such as metastatic urothelial tumors [31, 32]. Nab-pacli- taxel was developed to circumvent the highly hydrophobic properties of taxanes and to improve intratumoral paclitaxel penetration [30, 33]. Since it is devoid of Cremophor EL® (the solvent for paclitaxel), several significant adverse events such as hypersensitivity reactions are less likely to develop [30]. Nail toxicity has only been sporadically reported with nab-paclitaxel, especially onycholysis, and is easily manage- able [34]. The overall incidence of all-grade nail toxic effects with nab-paclitaxel is significantly lower in comparison with paclitaxel or docetaxel (19.4%) (95% CI: 11.8-30.3%) [35]. Vinca Alkaloids: Vincristine Vinca alkaloids were historically extracted from the leaves of the Madagascar periwinkle (Catharanthus roseus). Vin- cristine has been approved for intravenous use in the United States and is often used in combination chemotherapy regi- mens because of its lack of myelosuppression. Vincristine is commonly used to treat acute lymphocytic leukemia, multi- ple myeloma, chronic lymphocytic leukemia, lymphoblastic crisis of chronic myelogenous anemia, sarcomas, and small cell lung cancer with distant metastases [12]. Vincristine may cause diffuse hyperpigmentation, longitudinal melanony- chia, Beau’s lines, onychomadesis, Mees’ lines or Muehrcke’s lines (Table 2). Topoisomerase Inhibitors Topoisomerase II: Etoposide Etoposide is an inhibitor of the enzyme topoisomerase II, which relieves the helical strain during DNA replication by cutting both strands of DNA simultaneously. Topoisomerase Review | Dermatol Pract Concept. 2023;13(1):e2023064 7 Bruton’s Tyrosine Kinase (BTK) Inhibitors Bruton’s tyrosine kinase inhibitor, ibrutinib, is a small molecule that binds to a protein, important in B-cells. It is used for the treatment of chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, refractory and relapsed mantle-cell lymphoma. Brittle nails are the most common nail change, seen in about 2/3 of treated patients, followed by onychoschizia, onychorrhexis and mild onycholysis [38] (Table 3). Anti-HER2/Anti-HER Anti-human epidermal growth factor receptor 2 (Anti-HER2) is a class of medicines used to treat all stages of HER2-pos- itive breast cancer, from early-stage to metastatic disease. Trastuzumab was shown to cause thin nails [37, 38]. lapati- nib (breast cancer and solid tumors), afatinib (NSCLC) and dacomitinib (NSCLC), besides thin nails, may induce nail reactions such as paronychia, pyogenic granuloma, slower growth rate and mild onycholysis [37, 38] (Table 3). Anti-MEK Mitogen-activated protein kinase enzymes MEK1 and/ or MEK2, trametinib (metastatic melanoma), cobimetinib (melanoma) and selumetinib (Neurofibromatosis type I with antibacterial soaks (chlorhexidine or vinegar in water) [38]. Warm compresses, silver nitrate, topical corticosteroids and systemic tetracyclines are recommended in order to re- duce periungual inflammation, depending on the grade of the toxicity. Angiogenesis-Inducing Inhibitors Sorafenib and sunitinib are multikinase inhibitors that spe- cifically target tumor cell angiogenesis and proliferation via VEGFR (vascular endothelial growth factor), PDGRF (platelet-derived growth factor receptor) and other kinases [38]. Sorafenib is indicated in renal cell carcinoma, non- small cell lung cancer, hepatocellular carcinoma, melanoma, pancreatic and colon cancers, whilst sunitinib is prescribed for renal cell carcinoma, breast cancer, colon cancer and gas- trointestinal stromal tumor. Both are orally administered. Studies report that during the first 2 months of therapy, 70% and 25% of patients taking sorafenib and sunitinib, respec- tively, developed fingernail subungual splinter hemorrhages [41] (Table 3). The latter resolved spontaneously without treatment. This may be linked to the role VEGFR play in the renewal of capillaries and their sustain despite frequent injuries at the distal fingers, which is now inhibited due to sorafenib and sunitinib intake [38, 41]. Figure 2. Nail toxicities due to targeted biologic drugs. A. Paronychia due to treatment with EGFR tyrosine kinase inhibitor (panitumumab) for colorectal cancer: proximal nail fold is painful, erythematous and swollen with presence of oozing and crusting, B. Same patient as a.: close-up to a pyogenic granuloma that frequently accompanies paronychia due to EGFR inhibitors. C and D. Clinical and dermoscopy image of brittle nails during EGFR inhibitor therapy for lung cancer. The nail plate is fragile and the surface of the nail presents longitudinal fine fissures while the distal edge of the plate appears to crumble and is not sharply delineated. In dermoscopy presence of splinter hemorrhages can also be detected. E and F. Acute photo-onycholysis in a melanoma patient treated with BRAF inhibitors: clinical and dermoscopic image. The nails were extremely painful with almost total detachment of the nail plate and presence of oozing and subungual hematoma. 8 Review | Dermatol Pract Concept. 2023;13(1):e2023064 complex, certain types of seizures in adults and children and prevention of transplant rejection), as well as temsirolimus (indicated in renal cell carcinoma), may cause yellow nail dis- coloration, paronychia, pyogenic granuloma, slower growth rate-thin nails, mild onycholysis and brittle nails [38] (Table 3). RET Inhibitor RET inhibitors are targeted therapies used on tumors charac- terized by activated alterations in the RET proto-oncogene. These include non-small cell lung cancer (NSCLC), medul- lary thyroid cancer and papillary thyroid cancer. treatment) have been associated with paronychia, pyogenic granuloma, slower growth rate, mild onycholysis and brittle nails [38, 41]. M-TOR Inhibitors The mammalian target of rapamycin regulates cellular metabolism, growth and proliferation by forming and signal- ling through two protein complexes, mTORC1 and mTORC2 [38]. Everolimus (indicated in advanced renal cell carcinoma, advanced breast cancer, pancreas, stomach, intestines, lungs, subependymal giant cell astrocytoma, tuberous sclerosis Table 3. Main nail toxicities induced by targeted anticancer therapies [38]. Drug Class Target Chemotherapeutic Drugs Nail Disorders Anti-EGFR EGFR (HER1 or ErbB1) Cetuximab Panitumumab, Erlotinib Gefitinib Necitumumab Paronychia Pyogenic granuloma Slower growth rate Mild onycholysis Thin nails Brittle nails Anti-HER2 HER2 Trastuzumab Thin nails Anti-HER HER1-4 (ErbB1-4) Lapatinib Afatinib Dacomitinib Paronychia Pyogenic granuloma Slower growth rate Mild onycholysis Thin nails Brittle nails Anti-MEK MEK 1/2 Trametinib Cobimetinib Selumetinib Paronychia Pyogenic granuloma Slower growth rate Mild onycholysis Brittle nails mTOR inhibitors mTOR Everolimus Temsirolimus Paronychia Pyogenic granuloma Yellow nail discoloration Slower growth rate-thin nails Mild onycholysis Brittle nails Angiogenesis multikinase inhibitors VEGRF 1-3 PDGFR α/β and other molecular targets Sunitinib Sorafenib Cabozantinib Axitinib Pazotinib Regorafenib Splinter subungual hemorrhage Brittle nails RET inhibitor EGFR VEGFR 2/3 RET Vandetanib Paronychia Pyogenic granuloma Photoonycholysis Splinter subungual hemorrhage BCR-ABL inhibitor BCR-ABL c-KIT PDGFR Imatinib Melanonychia Lichenoid reactions Bruton inhibitors Bruton tyrosine kinase Ibrutinib Brittle nails Onychoschizia Onychorrhexis Mild onycholysis Review | Dermatol Pract Concept. 2023;13(1):e2023064 9 very rare but may provoke a destruction of the matrix and a subsequent scar formation. Immunotherapy (Figure 3) The immune system, as part of its normal function, detects and destroys abnormal cells and prevents or suppresses can- cer growth. Despite that, cancer cells have ways to evade the immune system. They may present genetic changes that make them less visible to the immune system, have proteins on their surface that turn off immune cells or affect the nor- mal cells surrounding a tumor in a way that they interfere with the immune response to cancer cells. The most prevalent immune-related dermatologic ad- verse events (irAE) are triggered by immune checkpoint in- hibitors (CPIs). Immune Checkpoint Inhibitors (CPIs) are targeted molecules that modulate the immune system, assist with self-tolerance, and minimize collateral tissue damage when immune responses are activated. These checkpoints are a nor- mal part of the immune system and keep immune responses from being too strong. By blocking them, these drugs allow immune cells to respond more efficiently to cancer. This blockade has been associated with autoimmune-like toxic- ities, named immune-related adverse events (irAE) [24, 43]. Vandetanib is an oral multikinase inhibitor which targets the RET, proto-oncogene, EGF and VEGF receptors. The most prevalent nail adverse event associated with Vande- tanib therapy is subungual hemorrhage (due to VEGFR inhi- bition), paronychia/pyogenic granuloma (EGFR inhibition) and a painful type 1 photo-onycholysis [38] (Table 3). Pa- tients should be informed about UVA/UVB photo-protection. BCR-ABL Inhibitors BCR-ABL is a gene produced by the BCR gene and the C-ABL proto-oncogene and is considered to be the main cause of chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL) that are Philadelphia chromosome-positive, certain types of gastrointestinal stromal tumors, hypereosin- ophilic syndrome, chronic eosinophilic leukemia, systemic mastocytosis and myelodysplastic syndrome [38]. Imatinib is an oral medication of this group that may induce mela- nonychia and lichenoid reactions (Table 3). Melanonychia appears 1-2 months after treatment initiation. It results from the direct toxic action of the regimen on the melanocytes of the nail matrix, with secondary melanin production. Mela- nonychia striate, as well as total melanonychia do not require any treatment. They regress spontaneously several months after treatment discontinuation [38]. Lichenoid reactions are Figure 3. Nail toxicities due to immunotherapy. A. Psoriatic changes in nails following treatment with immune checkpoint inhibitor ( pembrolizumab): presence of subtle pitting, onycholysis and paronychia with scaling of the skin. B. Same patient as a, dermoscopic image: Remark the presence of splinter hemorrhages as well as the yellow discoloration of the onycholysis suggestive of psoriatic disease. C, D. Lichenoid-like reactions in a melanoma patient treated with nivolumab: Onychorhexis visualized both clinically and with dermoscopy. In the dermoscopic image the presence of dust in the nail fissures gives the characteristic image of “dirty nail” that is a common finding in lichen-like reactions of the nail plate. E, F: Same patient as c, d different nails, dermoscopic images. Characteristic presence of erythema in the lunula seen in patients treated with nivolumab. 10 Review | Dermatol Pract Concept. 2023;13(1):e2023064 First-line treatment for these nail changes is topical ther- apy. If topicals fail and there is also skin involvement, sys- temic therapy should be considered [43, 45]. Pathogenesis of certain nail changes and potentially re- sponsible anticancer drugs. Table 4 highlights the diagnostic challenges related to drug-induced nail toxicities. Melanonychia Melanonychia represents one of the most common adverse effects of chemotherapeutic agents. Saraswat et al. [4] and Pavey et al. [1] found nail hyperpigmentation as the most common nail toxicity of chemotherapeutic drugs. This pig- mentation develops after 1–2 months of treatment and is proposed to be the outcome of matrix melanocyte activation, which usually affects several nail plates. Nail melanocytes are quiescent and generally do not produce melanin. Mela- nonychia results from the direct toxic action of chemother- apy on the melanocytes of the nail matrix, with secondary melanin production analogous to that of post-inflammatory hyperpigmentation seen in the skin [46- 49]. The activation of a subgroup of melanocytes produces a single or several longitudinal pigmented bands (melanony- chia striata) whereas diffuse activation of melanocytes gives rise to diffuse nail pigmentation (total melanonychia). Trans- verse melanonychia may also be observed [2]. Skin or muco- sal pigmentary changes are frequently associated. Nail hyperpigmentation is more often reported with che- motherapeutic agents like cyclophosphamide, cisplatin, fluo- rouracil and its prodrug capecitabine, taxanes, doxorubicin, bleomycin and Imatinib [16, 38, 50- 54] (Table 5). Chemo-induced hyperpigmentation does not require any treatment and progressively regresses several months after treat- ment discontinuation. For patients who would like to conceal this melanonychia, dark-colored nail polish may be proposed. Beau’s Lines Beau’s lines correspond to the formation of transverse lin- ear depressions in the dorsum of the nail plate and result from a transitory decrease in mitotic activity of the proximal nail matrix keratinocytes. The depth of the groove is strictly Immune checkpoints include cytotoxic T-lymphocyte an- tigen 4 (CTLA-4), programmed cell death 1 (PD-1) and pro- grammed cell death ligand 1 (PD-L1). The CTLA-4, PD-1, and PD-L1 pathways mediate immune responses at different levels. CTLA-4 controls the amplitude of immunologic re- sponse at early stages of T-cell activation, whereas PD-1 and PD-L1 pathways act at later stages, limiting T- cell activity in the peripheral tissues. By activating cytotoxic CD4+/CD8+ T cells, immune checkpoint blockade therapy shifts the im- mune system towards anti-tumor activity [42- 44]. The etiopathogenetic mechanism seems to be con- nected to the T-cell activation, mediated by the blockade of PD-1/PD-L1 and CTLA-4 receptors. CPIs include anti-PD-1 (nivolumab and pembrolizumab) and anti-CTLA-4 (ipilimumab, tremelimumab) agents, as well as the newly developed anti-PD-L1 agents (atezoli- zumab, durvalumab, avelumab) [42- 44]. ICIs nail alterations have not been systemically investi- gated and are considered uncommon. Nail toxicity presents late in time, with an onset extended up to several months from ICI initiation [42, 43]. Persistence of the nail change after ICI discontinuation has been also reported. Diverse nail changes have been reported in relationship to ICIs, including onycholysis, onychomadesis, longitudinal fissures, onychorrhexis, layered splitting of the nail plate, lunular erythema, thinning of the nail plate and fragility. Commonly, more than one finger- or toenails are involved. Nail psoriasis is the most common immunotherapy-related toxicity [42, 45]. Since the majority of nail alterations appear in conjunc- tion with psoriasiform or lichenoid rashes, they are most probably of the same nature. In line with this theory are the histopathologic alterations found in two patients exhibiting onycholysis that were consistent with lichenoid reaction. This develops either as a deterioration of pre-existing nail psoriasis, or as a de-novo appearance. Histopathologically confirmed psoriasis of the nail has been described in associa- tion with nivolumab, clinically characterized by nail thicken- ing combined with periungual erythema [43, 45]. Table 4. Challenges in the diagnosis of drug-induced nail toxicity. Several factors may pose diagnostic difficulties in the scenario of drug-induced nail toxicity [2, 3, 7, 81] 1. Nail changes may appear several weeks after drug intake, due to the kinetics of nail formation and the slow growth rate of the nail plate 2. Patients are often on multiple potentially causative medications 3. Symptoms often improve or resolve without drug withdrawal 4. Rechallenge is commonly uneventful 5. Non-drug causes may be involved 6. Abnormalities do not necessarily involve all nails 7. Poor understanding of the pathogenesis of nail damage. Review | Dermatol Pract Concept. 2023;13(1):e2023064 11 Table 5. Nail changes presented in association with the potentially responsible anticancer regimen. Nail Changes Conventional Chemotherapeutic Drugs Targeted Chemotherapeutic Drugs Diffuse hyper-pigmentation Cyclophosphamide, vincristine, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, capecitabine, doxorubicin, daunorubicin, bleomycin, hydroxyurea, busulfan, docetaxel, paclitaxel, pemetrexed, etoposide combination of cyclophosphamide/adriamycin/ vincristine/cyclophosphamide/adriamycin/ docetaxel Imatinib Longitudinal melanonychia Cyclophosphamide, vincristine, bleomycin, tegafur, combination of cyclophosphamide/ adriamycin/vincristine Imatinib Beau’s lines Docetaxel, paclitaxel, cisplatin, doxorubicin, bleomycin, combination of epirubicin/ vincristine/cyclophosphamide cyclophosphamide/doxorubicin/fluorouracil Onychomadesis Paclitaxel, docetaxel, capecitabine, combination of cyclophosphamide/vincristine/procarbazine/ prednisolone Mees’ lines Cyclophosphamide, doxorubicin, vincristine, docetaxel, paclitaxel, combination of cytarabine/ daunorubicin cyclophosphamide/doxorubicin/vincristine/ prednisolone (CHOP) Muehrcke’s lines Combination of cyclophosphamide/ doxorubicin/5-fluorouracil vincristine/doxorubicin/dexamethasone cisplatin, oxaliplatin Half and half nails (Lindsay’s nails) 5-Fluorouracil Onycholysis Docetaxel, paclitaxel, cyclophosphamide, pemetrexed, 5-fluorouracil, capecitabine Cetuximab, panitumumab,erlotinib, gefitinib, necituumab, lapatinib, afatinib, dacomitinib, trametinib, cobimetinib, selumetinib, everolimus, temsirolimus, ibrutinib, vandetanib Paronychia Fluorouracil, docetaxel, paclitaxel, etoposide Cetuximab, panitumumab,erlotinib, gefitinib, necituumab, lapatinib, afatinib, dacomitinib, trametinib, cobimetinib, selumetinib, everolimus, temsirolimus, vandetanib Subungual hyperkeratosis Docetaxel, paclitaxel, fluorouracil Pyogenic granuloma Docetaxel, paclitaxel Cetuximab, panitumumab,erlotinib gefitinib, necituumab, lapatinib, afatinib, dacomitinib, trametinib, cobimetinib, selumetinib, everolimus, temsirolimus, vandetanib Subungual & splinter hemorrhage Docetaxel, paclitaxel Vandetanib, sunitinib, sorafenib, cabozantinib, axitinib, pazotinib, regorafenib Brittle nails Docetaxel, paclitaxel Cetuximab, panitumumab,erlotinib, gefitinib, necituumab, lapatinib, afatinib, dacomitinib, trametinib, cobimetinib, selumetinib, everolimus temsirolimus, ibrutinib, sunitinib, sorafenib, cabozantinib, axitinib, pazotinib, regorafenib Onychorrhexis Docetaxel, paclitaxel Ibrutinib Koilonychia Docetaxel, paclitaxel 12 Review | Dermatol Pract Concept. 2023;13(1):e2023064 True Leukonychia (white opaque coloration - total or transverse: Mees’ lines) results from altered keratinization of the distal nail matrix. Parakeratotic nuclei are retained in the nail plate and thus the nail appears opaque and white in color owing to the diffraction of light by parakeratotic cells. True leukonychia does not disappear with pressure and moves distally as the nail grows. Mees’ lines are trans- verse white, non-blanching parallel lines to the lunula across the entire nail bed and have no palpable ridges [63, 64]. In chemotherapy-induced true transverse leukonychia, the ses- sions of transverse white bands and the distance between them seemed to coincide with the number and duration of chemotherapy cycles, respectively. Apparent Leukonychia (white transparent coloration) is observed because of changes in the nail bed vasculature on pressure, visible through the translucent nail plate. True and apparent leukonychia may be differentiated clinically by diascopy. The whitish discoloration disappears (or fades) with digital compression and is not modified by nail growth. Apparent leukonychia can present as three different clinical types: Muehrcke’s lines (the most frequent form in associ- ation with chemotherapy), Half and half nails (Lindsay’s nails), or Terry’s nails. a. Muehrcke’s Lines (the most frequent form in associa- tion with chemotherapy) are present as multiple, paired, transverse, whitish bands, parallel to the lunula. Chen et al. [6] found Muehrcke’s lines as the most common nail toxicity of chemotherapeutic drugs in children. This change is commonly seen after chemotherapy and in chronic hypoalbuminemia of less than 2 mg/dl (seen in nephrotic syndrome, glomerulonephritis, liver disease, and malnutrition), and is commonly found on the sec- ond, third, and fourth fingernails. Thumbnail involve- ment is rare. The lines tend to resolve with correction of hypoalbuminemia. The exact pathogenesis is unknown, but the suggested reasons are edema of the nail bed, which occurs due to hypoalbuminemia, and an alteration of nail plate attachment to the nail bed, which occurs due to vascular compromise following chemotherapy [6]. b. Half and Half Nails (Lindsay’s nails) where there is a definite border between the proximal area (opaque white) and the distal area (pink or reddish brown) occu- pying 20%–60% of the nail bed. Distal red-brown pig- mentation does not fade with pressure. c. Terry’s Nails, where the whole nail appears white, ex- cept a 1–2 mm pink-to-brown distal band, and the lunula may or may not be visible. In most cases, leukonychia involves all fingernails and may coexist with melanonychia. It has been described in association with numerous chemotherapeutic agents but correlated to the extent of nail matrix damage. The width is proportional to the duration of the insult. Beau’s lines have been described with nearly all chemotherapeutic agents, especially when used in combination or with a high-dose regimen. They are probably the most frequent nail changes noted in patients exposed to chemotherapy [46- 48]. Beau’s lines often affect all nails but are more frequent in finger- nails and appear after a few weeks of chemotherapy [4, 55]. After repeated courses of chemotherapy, several depressions can be noted in the same nail. They move distally with nail growth. The presence of regular transverse Beau’s lines in the nail plate reflects the temporary cessation of matrix prolif- eration during each chemotherapy cycle. Chemotherapeutic agents such as docetaxel, paclitaxel, a combination of epiru- bicin/vincristine/cyclophosphamide, and cyclophosphamide/ doxorubicin/fluorouracil are associated with Beau’s lines [4, 56, 57] (Table 5). Onychomadesis Onychomadesis is a spontaneous separation of the nail plate from the nail bed in its proximal portion. It implies a limited lesion affecting the proximal part of the matrix. It results from temporary cessation of nail growth lasting for more than 2 weeks. Initially, a small cleavage appears under the proximal portion of the nail. This forms a shallow ulcer that does not involve the deeper layers. When the injury is healed, the nail regrows over again distally. In latent onychomadesis, the nail plate demonstrates transverse split because of com- plete inhibition of nail growth for 1–2 weeks. Beau’s lines may evolve into the formation of onychomadesis, which essentially corresponds to the extreme form of Beau’s lines. The nail plate is then divided into two parts by a transverse thick groove, which remains latent for a long period before the nail plate ultimately sheds [58]. Onychomadesis induced by chemotherapeutic agents is thought to be the result of arrested mitotic activity in the nail matrix resulting in nail separation and shedding [59, 60]. Onychomadesis induced by chemotherapeutic agents was originally described by Kochupillai et al [61]. Since then only five cases have been reported in the literature. In Saras- wat et al. the drugs associated with the development of on- ychomadesis were imatinib, paclitaxel, capecitabine, and a combination of cyclophosphamide/vincristine/procarbazine/ prednisolone (Table 5). Leukonychia Leukonychia is characterized by white discoloration of a part of the nail plate or the complete nail plate, and can be divided into true leukonychia and apparent leu- konychia. Leukonychia induced by chemotherapeutic agents usually occurs in the form of apparent leukonychia [10, 46- 48, 62]. Review | Dermatol Pract Concept. 2023;13(1):e2023064 13 cycles given and the cumulative dose of taxanes [29, 46, 47, 59]. Although it is more common in patients receiving the once-weekly regimen, it can also be observed with the every 3-week regimen [29, 46]. The onycholytic portion of the nail plate becomes opaque, loses its translucency, and can take on a white, black, or brown-red color, depending on the type of lesion [57, 59, 60]. The fingernails are more often involved than toenails and the number of digits affected varies, although involvement may also be diffuse [29, 59, 69- 72]. Onycholy- sis is initially asymptomatic; however, pain may occur due to acute trauma, progression of the detachment, or devel- opment of subungual hemorrhagic blisters or abscesses with purulent malodorous discharge (exudative onycholysis) [22, 26, 48, 60, 71]. Secondary bacterial or fungal infections may also develop because of the debris collected in the ventral part of the detached plate. Cosmetic and functional impacts depend on the number of nails involved, the severity of the detachment, and the extent of pain [29]. Taxane-related onycholysis is sometimes associated with inflammatory erythema of dorsal hands or the perimalleolar and Achille’s areas (PATEO syndrome: periarticular thenar erythema with onycholysis) [22, 24]. The changes may affect both the nail matrix (melanon- ychia, true leukonychia, Beau’s lines and onychomadesis, brittle nails with ridging and thinning, onychorrhexis, koil- onychias), the nail bed (onycholysis and apparent leukon- ychia) or the periungual tissue (paronychia or pyogenic granuloma), may also be affected at the same time with tax- ane chemotherapy [22, 24, 26, 47]. The pathophysiological origin of taxane-induced on- ycholysis is not clearly established. It may be the result of direct cytotoxic damage to the nail matrix and epithelial cells of the nail bed with epidermolysis and the secondary loss of adhesion of the nail plate to the nail bed [24, 47]. An intrinsic antiangiogenic activity of taxanes has also been postulated [22]. Similarly, a phototoxic mechanism for pho- to-onycholysis has been advanced by some authors but re- mains to be confirmed [59]. Lastly, unilateral onycholysis has been reported in patients suffering from contralateral periph- eral palsy, suggesting a taxane-induced neurotropic effect (neurogenic or prostaglandin-mediated inflammation) [73]. More recently, Schepisi et al. [34] hypothesized that paclitaxel-related onycholysis may be directly correlated to the duration of the infusion. Indeed, onycholysis may de- velop more frequently with a shorter infusion (1 hour) than with a prolonged infusion, because of increased systemic ex- posure to the Cremophor vehicle (paclitaxel solvent). That may explain, at least in part, the higher incidence seen in patients receiving the weekly paclitaxel regimen (1-hour infusion) in comparison with the every 3-week regimen (3-hour infusion). generally develops when chemotherapy is used in combina- tion. Systematic screening for associated hypoalbuminemia should be performed in this context. Mees’ lines are usually observed with the use of docetaxel and a combination of cytarabine/daunorubicin and cyclo- phosphamide/doxorubicin/vincristine/prednisolone [65- 67] (Table 5). Muehrcke’s lines have been reported with cispla- tin, oxaliplatin and a combination of cyclophosphamide/ doxorubicin/5-fluorouracil and vincristine/doxorubicin/ dexamethasone [68] (Table 5). Nail growth is faster in children and adolescents, and is estimated to be at a rate of 0.12 mm/day [23]. However, chemotherapy-induced nail changes in children, in compari- son to adult cases, are less well characterized in the literature. Reviewing the limited case reports, transverse leukonychia seems to be the most frequently described nail change in children receiving chemotherapy, with doxorubicin/dauno- rubicin, vincristine and cyclophosphamide being the main causative agents [23, 66]. Onycholysis Onycholysis is defined by the separation of the nail plate from the underlying nail bed [48]. It usually starts from the distal portion of the nail bed, progresses proximally, and can involve the entire nail with the formation of a space. This may result in the formation of painful subungual abscesses and hemorrhages and finally loss of the nail plate. It is notewor- thy that the chemotherapeutic agents that most frequently induce nail changes are taxanes: docetaxel and paclitaxel, resulting from a direct toxic effect [22, 25, 26, 46, 59]. However, mild to moderate onycholysis may also be noted with other chemotherapeutic agents as well (capecit- abine, etoposide, cytarabine, cyclophosphamide, doxoru- bicin, or combination therapy) [24, 46, 48]. The targeted chemotherapeutic agents, which may cause onycholysis are cetuximab, panitumumab, erlotinib, gefitinib, necitumumab, lapatinib, afatinib, dacomitinib, trametinib, cobimetinib, selumetinib, everolimus, temsirolimus, ibrutinib and vande- tanib [38] (Table 5). Onycholysis is one of the most prevalent adverse events induced by docetaxel or paclitaxel [22]. Recently, the over- all incidence of taxane-induced nail toxicity has been sys- tematically investigated [35]; all-grade incidence was 43.7% with paclitaxel (95% CI: 18.0-73.3%) and 34.9% (95% CI: 29.9-40.2%) with docetaxel. For the latter, the relative risk was 77.74 (95% CI: 41.88-144.32; p<0.001) as compared to controls [22]. Nail changes are evident after several weeks of treat- ment because of the slow growth rate of the nail plate [29]. The development of nail changes is strongly associated with weekly administration, the number of chemotherapy 14 Review | Dermatol Pract Concept. 2023;13(1):e2023064 Onychorrhexis is a type of longitudinal groove wherein a series of shallow and narrow furrows are present running parallel on the nail surface. Docetaxel, paclitaxel and ibruti- nib may cause onychorrhexis (Table 5). Onychoschizia is clinically characterized by the splitting of the nail plate at the free edges in the fingers and toes. It may be localized or the full length of the free edge may be involved. Electron microscopy reveals horizontal separation of the nail plate, which may, sometimes, extend up to the proximal nail fold. It also demonstrates individual cells ly- ing in the empty spaces. These observations indicate lamellar splitting in onychoschizia occurs between the cell layers. Management and Prevention Counselling for the prevention of nail toxic effects is man- datory. Healthcare professionals should provide patients with clear and detailed information. The patients should avoid re- peated trauma or pressure on nails and nail beds or irritant regimen, including manipulation of the cuticles and nail bit- ing, use of fingernails as “tools,” prolonged soaking in water, exposure to solvents or hard chemicals, and application of ar- tificial nails. They are encouraged to trim their nails regularly and smooth the edges. The nails should be straight/squared and not too short. Prophylactic measures include the use of cotton gloves, comfortable wide-fitting footwear and cotton socks. Housework should be performed only with glove pro- tection. When UV-associated toxicity is related to the drug regimen patients should be informed and wear gloves when outside. Nail lacquers are recommended to limit water loss from the nail plate (especially for brittle nails). Furthermore, daily use of topical emollients on the total nail apparatus (cu- ticles, plate, and periungual folds) is a prophylactic manage- ment for chemotherapy-induced nail toxicity [48]. In addition, Scotté et al. [25] have demonstrated that the preventive use of frozen gloves/socks in patients treated with docetaxel al- lowed a significant reduction in changes from 51% to 11% (p=0.0001) in fingernails, and from 21% to 0% in toenails, with a trend towards a prolongation (albeit non-significant) of the median time to development of these lesions. Importantly, the Grade 2 or greater nail AEs were reduced from 22% to 0% (p=0.0001) [25, 69]. Therefore, the preventive use of fro- zen gloves/socks should be advised in patients treated with taxanes [25]. Alternatively, the use of ice packs may be a less expensive and effective strategy with similar efficacy [27]. In addition to preventing nail toxicities, frozen gloves or ice packs have been shown to decrease the incidence of peripheral neuropathy, another potentially dose-limiting adverse event. It is intriguing that despite the simplicity and effectiveness of this intervention, it is not universally employed. In case onycholysis develops, excising the nail plate (par- tially or totally) may be necessary (Figure 4), especially in se- vere and painful lesions, or when associated with a pressure The impact of taxane-related onycholysis on the quality of life and daily activities varies; effects depend on the number of digits involved, the degree of detachment, and the extent of pain and if significant it can result in treatment interruption [28, 29]. Therefore, management of onycholysis depends on the clinical grading (i.e., National Cancer Institute, Common Terminology Criteria for Adverse Events (CTCAE) v4.02) and impact on activities of daily living [38] (Table 1). Ony- cholysis is slowly reversible after treatment, however chronic onycholysis can lead to nail bed keratinization and persistent subungual hyperkeratosis [22, 74]. Therefore, it is crucial to promote nail reattachment as early as possible by preventing further toxicity and treating underlying infections, otherwise onycholysis may become permanent. Paronychia Paronychia is the result of inflammation of proximal/lateral nail folds with erythema, edema, tenderness or pain of the nail folds and impaired activity. It usually develops soon af- ter intake of the drug, involves one or several nails and is thought to be the result of the toxic effect of the drug on nail epithelium [2, 8]. Paronychia is a frequent but uncommonly reported adverse effect of epidermal growth factor inhibitors which is the result of aberrant vascular response affecting nail folds [75, 76]. Except for anti-EGFR targeted therapy, RET inhibitor, mTOR inhibitors, anti-MEK, anti-HER, 5-fluorouracil and docetaxel have been reported to develop paronychia as well [4] (Table 5). Brittle Nails and Decreased Nail Growth A decrease in nail plate growth is commonly noted with che- motherapy, although it will usually go unnoticed by patients or physicians. The nails are often fragile and thinner, which can lead to koilonychia, onychorrhexis, or onychoschizia af- ter several cycles of chemotherapy [74]. Chemotherapeutic agents such as cetuximab, panitumumab, erlotinib, gefitinib, necitumumab, lapatinib, afatinib, dacomitinib, trametinib, cobimetinib, selumetinib, everolimus, temsirolimus, ibruti- nib, sunitinib, sorafenib, cabozantinib, axitinib, pazotinib, regorafenib, docetaxel and paclitaxelare associated with brittle nails (Table 5). Koilonychia is a common nail dystrophy in which the dorsal surface of the nail plate becomes flat or truly concave. It is derived from the Greek word koilos, meaning hollow. Pathogenesis of koilonychia is not known but it is sug- gested that anoxia and atrophy of the distal matrix are con- tributory. Koilonychia is the converse of clubbing and it is more appreciated when viewed from the side. When a drop of water is put on the surface, it will not fall off. It should be noted that nails in koilonychia are brittle. It is commonly seen in fingernails rather than toenails. Docetaxel and Pacli- taxel may cause koilonychia more often (Table 5). Review | Dermatol Pract Concept. 2023;13(1):e2023064 15 Cryotherapy’s effect is related to cold-induced vasocon- striction, which reduces the quantity of drugs reaching the proliferating stem cells. For patients who can afford them, tolerate discomfort and exhibit compliance, these prophy- lactic managements of taxane-induced nail toxicity can be suggested as an option to improve patients’ quality of life and functional statuses. However, future investigations and studies are needed to establish the routine usage protocols, standard outcome measures, long-term efficacy and safety for these interventions [77]. Conclusions A wide spectrum of nail toxicities has so far been described in association with both, conventional and newer antican- cer agents; however, less importance has been given to nail changes as compared to other skin toxicities. Considering that nail toxicity is indeed almost never life-threatening, dis- continuation of oncologic therapy is only rarely necessary. However, drug interruptions or dose modifications may be warranted, mostly due to serious impairment of patients’ quality of life. Management is primarily directed at symp- tom control and relief of the patient. Nail changes that re- sult from matrix interruption of blood flow often induce cosmetic changes (not requiring intervention), with the nail eventually growing out normally after treatment discontin- uation. On the other hand, nail changes due to disruption of the nail folds frequently require therapeutic intervention, and depending on the severity, also dose modifications. hematoma or subungual abscess [7]. The nail bed should be cleaned and a sample for culture collected at the same time, and in case of suspected infection should be also promptly treated with topical/oral antibiotics antiviral or antifungal therapy [48]. The detached nails should be cut regularly until the nail plate grows and covers the nail bed. In the setting of paronychia without infection, potent topical steroids are recommended. Except for the aforementioned traditional management modalities, some other clinical methods, such as cryotherapy and nail solution (nail balm), have been reported and pro- moted. Huang et al. [77] in their meta-analysis revealed that both nail solution-based and cryotherapy-based prophylac- tic management (frozen gloves, frozen socks and ice packs) were effective for treating taxane-induced nail toxicity. Nail solution use is known to reduce the levels of substance P, a neurotransmitter that induces inflammation, which ad- versely affects nails [78]. Moreover, plant-based waxes and essential oils are naturally rich in phytochemicals, partic- ularly phenolic polyphenols, which have been reported to exhibit antioxidant, anti-inflammatory, DNA repair-enhanc- ing and antimicrobial properties [79, 80]. In addition to their abilities to moisturize the skin and prevent the drying and splitting of nails, the waxes and essential oils were hy- pothesized to be sufficiently absorbed into the nail beds to act as local antidotes to the chemotherapeutic agent, thus preventing damage to the proliferating stem cells, avoiding secondary damage from inflammation or secondary infec- tion as well as delaying the time to nail toxicity [79, 80]. Figure 4. A. Onycholysis due to taxane treatment. Observe important detachment of plate from bed and presence of purulent discharge, B. Clipping of the onycholytic part of the nails relieves pain and allows for better hygiene. 16 Review | Dermatol Pract Concept. 2023;13(1):e2023064 14. Dasanu CA, Wiernik PH, Vaillant J, Alexandrescu DT. A complex pattern of melanonychia and onycholysis after treatment with pemetrexed for lung cancer. Skinmed. 2007;6(2):95–6. 15. Malet-Martino M, Martino R. 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